This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There are approximately 400 million HBV chronic carriers worldwide, of whom about 1 million die annually from liver cancer and chronic disease. Co- or super-infection with hepatitis delta virus (HDV) can increase liver damage and risk of cirrhosis and hepatocellular carcinoma (HCC). This proposal is aimed to ascertain the molecular mechanism of HBV/HDV infection with emphasis on pathogenesis. The goal of Aim 1 is to understand the relationship between virus-induced pathogenesis and a particular genotype of HBV. The project will compare replication, assembly, and infectivity in primary human hepatocytes (PHH), and host response for all known 8 HBV genotypes. The studies proposed will: (i) facilitate understanding of the HBV genotype-specific pathogenesis;(ii) ascertain how HDV chronic infection is maintained;(iii) have a serious impact on understanding of virus[unreadable]host interactions. The finding of the most infectious HBV genotype will facilitate: development of more potent peptide antivirals;microarray studies using the system of in vitro infection of PHH;establishment of HBV-susceptible cell lines. Aim 2 will delineate significance of the balance between HBV and HDV for outcome of infection. It is proposed to quantitatively examine what regulates competition or homeostasis between the two viruses during co-assembly. Also, using PHH, the patterns of co- and super-infection will be analyzed, addressing if the two viruses compete for susceptible cells, and if their replication rates are mutually affected. These studies will: (i) facilitate building the model of HBV-HDV homeostasis;(ii) enhance understanding of virus-virus interactions in relation to pathogenesis;(iii) clarify the mechanism of chronic infection.